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- EMDB-10575: PKM2 in complex with Compound 5 -

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Basic information

Entry
Database: EMDB / ID: EMD-10575
TitlePKM2 in complex with Compound 5
Map dataNone
Sample
  • Complex: Pyruvate Kinase M2
    • Protein or peptide: Pyruvate kinase PKM
  • Ligand: 5-hydroxynaphthalene-1-sulfonamide
  • Ligand: 1,6-di-O-phosphono-beta-D-fructofuranose
  • Ligand: water
KeywordsPKM2 / FBDD / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


pyruvate kinase / pyruvate kinase activity / Pyruvate metabolism / histone H3T11 kinase activity / programmed cell death / positive regulation of cytoplasmic translation / canonical glycolysis / Glycolysis / positive regulation of sprouting angiogenesis / potassium ion binding ...pyruvate kinase / pyruvate kinase activity / Pyruvate metabolism / histone H3T11 kinase activity / programmed cell death / positive regulation of cytoplasmic translation / canonical glycolysis / Glycolysis / positive regulation of sprouting angiogenesis / potassium ion binding / rough endoplasmic reticulum / Regulation of pyruvate metabolism / glycolytic process / non-specific protein-tyrosine kinase / cilium / cellular response to insulin stimulus / extracellular vesicle / MHC class II protein complex binding / protein tyrosine kinase activity / collagen-containing extracellular matrix / secretory granule lumen / vesicle / ficolin-1-rich granule lumen / transcription coactivator activity / non-specific serine/threonine protein kinase / cadherin binding / mRNA binding / Neutrophil degranulation / magnesium ion binding / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / mitochondrion / RNA binding / extracellular exosome / extracellular region / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Pyruvate kinase, active site / Pyruvate kinase active site signature. / Pyruvate kinase / Pyruvate kinase, barrel / Pyruvate kinase, insert domain superfamily / Pyruvate kinase, barrel domain / Pyruvate kinase, C-terminal / Pyruvate kinase, C-terminal domain superfamily / Pyruvate kinase, alpha/beta domain / Pyruvate kinase-like, insert domain superfamily ...Pyruvate kinase, active site / Pyruvate kinase active site signature. / Pyruvate kinase / Pyruvate kinase, barrel / Pyruvate kinase, insert domain superfamily / Pyruvate kinase, barrel domain / Pyruvate kinase, C-terminal / Pyruvate kinase, C-terminal domain superfamily / Pyruvate kinase, alpha/beta domain / Pyruvate kinase-like, insert domain superfamily / Pyruvate kinase-like domain superfamily / Pyruvate/Phosphoenolpyruvate kinase-like domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSaur M / Hartshorn MJ
CitationJournal: Drug Discov Today / Year: 2020
Title: Fragment-based drug discovery using cryo-EM.
Authors: Michael Saur / Michael J Hartshorn / Jing Dong / Judith Reeks / Gabor Bunkoczi / Harren Jhoti / Pamela A Williams /
Abstract: Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. ...Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).
History
DepositionDec 27, 2019-
Header (metadata) releaseJan 15, 2020-
Map releaseJan 15, 2020-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ttf
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10575.png

Downloads & links

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Map

FileDownload / File: emd_10575.map.gz / Format: CCP4 / Size: 175 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNone
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 134 pix.
= 133.42 Å		1 Å/pix.
x 112 pix.
= 111.515 Å		1 Å/pix.
x 95 pix.
= 94.589 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 0.99567 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04 / Movie #1: 0.04
Minimum - Maximum-0.18172021 - 0.2684847
Average (Standard dev.)0.0027029964 (±0.024734506)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions11295134
Spacing95112134
CellA: 94.58865 Å / B: 111.515045 Å / C: 133.41978 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.995673684210530.995669642857140.99567164179104
M x/y/z95112134
origin x/y/z0.0000.0000.000
length x/y/z94.589111.515133.420
α/β/γ90.00090.00090.000
start NX/NY/NZ1081340
NX/NY/NZ13584349
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS95112134
D min/max/mean-0.1820.2680.003

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Supplemental data

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Additional map: Relion post-process unmasked map

Fileemd_10575_additional.map
AnnotationRelion post-process unmasked map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Relion post-process unmasked map

Fileemd_10575_additional_1.map
AnnotationRelion post-process unmasked map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Relion auto-refine halfmap 1

Fileemd_10575_half_map_1.map
AnnotationRelion auto-refine halfmap 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Relion auto-refine halfmap 2

Fileemd_10575_half_map_2.map
AnnotationRelion auto-refine halfmap 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Pyruvate Kinase M2

EntireName: Pyruvate Kinase M2
Components
  • Complex: Pyruvate Kinase M2
    • Protein or peptide: Pyruvate kinase PKM
  • Ligand: 5-hydroxynaphthalene-1-sulfonamide
  • Ligand: 1,6-di-O-phosphono-beta-D-fructofuranose
  • Ligand: water

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Supramolecule #1: Pyruvate Kinase M2

SupramoleculeName: Pyruvate Kinase M2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 240 KDa

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Macromolecule #1: Pyruvate kinase PKM

MacromoleculeName: Pyruvate kinase PKM / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: pyruvate kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.83182 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLVPRGSK PHSEAGTAFI QTQQLHAAMA DTFLEHMCRL DIDSPPITAR NTGIICTIGP ASRSVETLKE MIKSGMNVA RLNFSHGTHE YHAETIKNVR TATESFASDP ILYRPVAVAL DTKGPEIRTG LIKGSGTAEV ELKKGATLKI T LDNAYMEK ...String:
MGSSHHHHHH SSGLVPRGSK PHSEAGTAFI QTQQLHAAMA DTFLEHMCRL DIDSPPITAR NTGIICTIGP ASRSVETLKE MIKSGMNVA RLNFSHGTHE YHAETIKNVR TATESFASDP ILYRPVAVAL DTKGPEIRTG LIKGSGTAEV ELKKGATLKI T LDNAYMEK CDENILWLDY KNICKVVEVG SKIYVDDGLI SLQVKQKGAD FLVTEVENGG SLGSKKGVNL PGAAVDLPAV SE KDIQDLK FGVEQDVDMV FASFIRKASD VHEVRKVLGE KGKNIKIISK IENHEGVRRF DEILEASDGI MVARGDLGIE IPA EKVFLA QKMMIGRCNR AGKPVICATQ MLESMIKKPR PTRAEGSDVA NAVLDGADCI MLSGETAKGD YPLEAVRMQH LIAR EAEAA IYHLQLFEEL RRLAPITSDP TEATAVGAVE ASFKCCSGAI IVLTKSGRSA HQVARYRPRA PIIAVTRNPQ TARQA HLYR GIFPVLCKDP VQEAWAEDVD LRVNFAMNVG KARGFFKKGD VVIVLTGWRP GSGFTNTMRV VPVP

UniProtKB: Pyruvate kinase PKM

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Macromolecule #2: 5-hydroxynaphthalene-1-sulfonamide

MacromoleculeName: 5-hydroxynaphthalene-1-sulfonamide / type: ligand / ID: 2 / Number of copies: 4 / Formula: LZ2
Molecular weightTheoretical: 223.248 Da
Chemical component information

ChemComp-LZ2:
5-hydroxynaphthalene-1-sulfonamide

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Macromolecule #3: 1,6-di-O-phosphono-beta-D-fructofuranose

MacromoleculeName: 1,6-di-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: FBP
Molecular weightTheoretical: 340.116 Da
Chemical component information

ChemComp-FBP:
1,6-di-O-phosphono-beta-D-fructofuranose

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 16 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.16 mg/mL
BufferpH: 8.2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 707 / Average exposure time: 37.06 sec. / Average electron dose: 54.85 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD

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Image processing

Particle selectionNumber selected: 371779
Startup modelType of model: OTHER / Details: in-house X-ray structure
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.04) / Number images used: 287873
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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